During the initial three years of work our studies focused on the humoral immune response in Multiple Sclerosis (MS). We found that the intrathecal synthesis of free kappa light chains manifest by markedly increased concentrations of free kappa chains in cerebrospinal fluid (CSF) was a consistent, early, and stable abnormality in MS patients. In contrast, we have not yet observed this abnormality in patients with noninfectious diseases of the nervous system; patients with culture-established CNS infections characteristically exhibited an IgG-lambda intrathecal humoral immune response. Thus, our work to date suggests that exaggerated intrathecal synthesis of free kappa chains is not only a consistent abnormality in MS, but is also remarkably specific for MS compared with the relative nonspecificity of other IgG abnormalities. Studies proposed for the subsequent three years of support will logically follow from the initial studies. We propose carefully- designed prospective clinical studies designed to determine the relevance of humoral immune abnormalities in Ms. First, we will conduct a prospective study to determine how to use CSF parameters to predict the rate and severity of disease progression in MS. This study is important because of our total inability to predict the likely disease severity in individual MS patient early in the course of this extremtly variable disease. In addition to causing distress for all concerned, this results in marked heterogeneity within groups in therapeutic trials, confounding interpretation of treatment efficacy. Second, we will determine the prognostic value of CSF IgG abnormalities in predicting progression to disseminated disease in individuals with monosymptomatic disease. Third, we will determine the optimal test or combination of tests for the diagnosis of MS in particular clinical settings. We will use receiver operating characteristics and decision analysis to propose clinically useful algorithms based on the generated data. These studies offer the promise of clarifying the clinical relevance of humoral immune abnormalities in the disease.